6. Jahrgang 2009 // Nummer 2 // ISSN 1810-2107
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2009
ReproduktionsmedizinNo.2
und Endokrinologie
– Journal of Reproductive Medicine and Endocrinology –
Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik
Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie
Metabolic Impact of Estrogen Replacement Therapy
Villa P, Moruzzi MC, Lassandro AP, Lanzone A
Mancuso S
J. Reproduktionsmed. Endokrinol 2010; 7 (Sonderheft
1), 119-124
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Metabolic Impact of HRT
Metabolic Impact of Estrogen Replacement Therapy
P. Villa1, M. C. Moruzzi1, A. P. Lassandro2, A. Lanzone1, S. Mancuso3
Menopause is associated with unfavourable changes in the blood lipid profile as well as with a deterioration of glucose tolerance, which may help in
increasing the incidence of cardiovascular diseases. In the same way Hormone Replacement Therapy (HRT) has different metabolic impact in relationship
to the dose of estrogen component, the type of progestin and the route of administration. Most of the studies analyzed the effect of the combined estroprogestin therapy, therefore, the impact of the estrogen component alone isn’t always differentiable but principal results are generally consistent. This
review aimes to expound the metabolic impact of the estrogen replacement administration in postmenopausal women. A literature review was conducted to identify all the prospective, the randomized trials and to compare the effects of both low and high-dose therapy and route of administration (oral
and transdermal). The results of estrogen replacement therapy on glucose metabolism showed minimal changes and differences among treatments.
Some studies showed that neither peroral nor transdermal estradiol replacement therapy induced any negative effects on glucose metabolism. The
estrogen substitution increases the rate of apolipoprotein metabolism in various degrees, depending on the type of lipoprotein. At present a considerable
data document an increase in HDL and a reduction of LDL cholesterol, following estrogen therapy. Studies have clearly established that the estrogen
treatment decreases total plasma cholesterol and increases or maintains plasma triglyceride levels. In conclusion the studies of ERT’s effects on glucose
and lipid metabolism are heterogeneous but all together the ERT impact may be considered neutral. However the low doses of estrogen therapy may give
some beneficial effects. Above all the treatment may prevent the physiological worsening of the glucose and lipid metabolism in menopause.
J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1): 119–24.
Key words: menopause, ERT, lipid metabolism, glucose metabolism
„ Introduction
Menopause is associated with unfavourable changes in the blood lipid profile as
well as with a deterioration of glucose
tolerance, factors that are likely to increase the incidence of cardiovascular
diseases [1].
These changes are in part due to the agerelated metabolic impairment, but may
also be associated with postmenopausal
hypoestrogenism [2].
The sharp decrease in circulating steroid
hormones seems to reduce both insulin
secretion and elimination, as well as to
increase insulin resistance, thereafter
bringing about an increase in the circulating insulin concentration and a higher
incidence of both type II diabetes and
metabolic syndrome [1].
Therefore the estrogen deficiency leads
to increased levels of Low-Density
Lipoprotein (LDL), total cholesterol, triglycerides, and lipoprotein(a) (Lp[a])and lowers the levels of High Density
Lipoprotein (HDL) [3]. Postmenopausal
women generally gain weight and show
an android fat distribution [4].
There is a persistent perception that estrogen administration may have deleterious effects on lipid and glucose metabolism; this belief dates back to observation of metabolic effects of high- estrogen oral contraceptive use and depending on steroid composition and dosage
[5]. In the same way, Hormone Replacement Therapy (HRT) has a different
metabolic impact depending on the dose
of the estrogen component, the type of
progestin and the route of administration. When evaluating metabolic effects
of HRT, it must be remembered that most
of the studies analyzed the effect of the
combined estro-progestin therapy; therefore, whereas the impact of the estrogen
component alone is not always measurable, results are nonetheless consistent.
In particular this review aims at summarising the metabolic impact of the estrogen replacement administration in postmenopausal women.
„ Estrogens and Carbohydrate Metabolism
Estrogens play a role in glucose homeostasis, possibly through an effect on insulin secretion and clearance. Postmeno-
pausal women have similar glucose and
insulin levels to premenopausal ones,
but produce 50 % less insulin and eliminate it slowly, thus compensating for the
reduced secretion [1].
Measurement of plasma insulin concentration alone is insufficient for the assessment of pancreatic insulin secretion,
because of the substantial and variable
uptake of newly secreted insulin by the
liver and its short half life. C-peptide is
secreted simultaneously with insulin and
in equimolar quantities but does not undergo liver uptake, therefore providing a
good index of insulin secretion. Moreover many models arising from Intravenous Glucose Tolerance Test (IVGTT)
or Oral Glucose Tolerance Test (OGTT)
have been developed to measure the
fraction of new secreted insulin passing
through the liver and the rate of elimination of insulin from the general circulation.
At the same time different indexes of insulin sensitivity have been assessed from
measurements in the fasting state and
during oral glucose tolerance test. The
most intensively validated among them
are HOMA-IR (HOmeostasis Model As-
Received and accepted: August 5, 2010.
From the 1Department of Obstetrics and Gynaecology, the 2Department of Endocrinology and the 3Ethical Committee, Policlinico “A. Gemelli” School of Medicine, Università
Cattolica del Sacro Cuore, Rome, Italy
Correspondence: Prof. Dr. Salvatore Mancuso, Via della Camilluccia 647, I-00135 Rome, Italy; e-mail: [email protected]
J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1)
For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.
119
Metabolic Impact of HRT
Table 1: Glucose metabolism and estrogen replacement therapy
Reference
No. of
subjects
Duration
of estrogen
Fasting
glucose
Fasting
insulin
AUC for
glucose
AUC for
insulin
Oral
CEE 0.625 mg
Cagnacci et al., 1992 [15]
Godsland et al., 1993 [1]*
15
30
3 months
3 months
È
N
N
Ç
Lobo et al., 1994 [14]
Espeland et al., 1998 [11]
29
97
12 months
36 months
È
È
È
È
N
N
1. phase È
2. phase N
È
95/89
12 months
N
N
N
N
N
35
6 months
N
N
N
N
N
43
3 months
N
N
N
N
È
40
12 months
È
È
N
N/È
Ç
48
3 months
N
È
N
N
Ç
15
30
9
9
21
22
38
3 months
3 months
3 months
2 months
12 weeks
6 weeks
6 months
N
È
N
N
N
N
N
N
N/È**
N
N
N
N
N
N
N
N
↓
N
N
N/È**
N/È
N
N
CEE 0.45–0.30 mg
Lobo et al., 1994 [14]
Estradiol
Karjalainen et al., 2001 [19]
(2 mg)
Soranna et al., 2002 [20]
(2 mg)
Li et al., 2003 [22]
(1 mg/NETA 0.5)
Villa et al., 2008 [21]
(1 mg)
Transdermal
Cagnacci et al., 1992 [15]
Godsland et al., 1993 [1]*
O’Sullivan & Ho, 1995
Cagnacci et al., 1997 [17]
Cucinelli et al., 1999 [16]
Duncan et al., 1999 [18]
Karjalainen et al., 2001 [19]
(1 mg)
Insulin
sensitivity
N
N
N
N
N/Ç
N
N
AUC: area under the curve; CEE: conjugated equine estrogen; N: no statistically significant change; Ç: increase; È: decrease.
* The women received combination therapy; these are the results of glucose metabolism studies at the end of the estrogen-alone phase;
** Decrease of insulin in oral glucose tolerance test, no change in intravenous glucose tolerance test.
sessment) and QUIKI (QUantitative Insulin sensitivity checK Index).
On the other hand the only direct measure of insulin sensitivity and the gold
standard for this measurement remains
the glucose clamp technique which determines the metabolic index (M) of insulin sensitivity.
„ Direct Effects on the Pancreas
doses and determines an increase in
growth hormone secretion, thereby influencing insulin secretion [8, 9].
In humans estrogens may determine
glucagone antagonism, a fact that may
explain the reduction in fasting plasma
glucose observed.
Estrogen deficiency is associated with
deterioration in glucose tolerance and
increased insulin resistance while estrogen replacement tends to annul these effects. Also an excess of estrogens is associated with deterioration in glucose
tolerance and insulin resistance. This
gradation in response to estrogens could
be also present for the insulin receptor
gene expression [10].
Estrogens may have direct effects on the
pancreas as well as an influence on other
hormones which themselves affect insulin secretion or action. Receptor binding
for estrogen is present in the pancreatic
islets and at this level estrogens can increase the presence of progesterone receptors; for this reason, progesterone exposure of isolated islets augments insulin release [6, 7].
„ Estrogen Replacement
Therapy
Estrogens administration increases glucocorticoid activity, especially in high
The “Postmenopausal Estrogen/Progestin Interventions (PEPI) study” was the
first placebo-controlled trial evaluating
120
J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1)
the effect of postmenopausal therapy on
glucose metabolism. Researchers found
a statistically significant decrease in fasting glucose levels over the 3 year duration of the study in patients who adhered to
their hormone therapy assignment [11].
Two additional randomized clinical trials, carried out with the primary purpose
of evaluating cardiovascular outcomes,
found unexpectedly a significantly
lower incidence of diabetes in patients
receiving HRT [12, 13].
The “Heart and Estro-progestin Replacement Study” (HERS) published data on
incidence of diabetes in 2029 postmenopausal women who had coronary heart
diseases and had been assigned daily to
0.625 mg of conjugated equine estrogens (CEE) plus 2.5 mg of medroxyprogesterone acetate (MPA) or to placebo [12]. The incidence of diabetes in
this 4-year study was 6.2 % in the treated
group compared to 9.5 % in the placebo
group (HR 0.65; 95 %-CI: 0.43–0.89).
Metabolic Impact of HRT
Also the Women’s Health Initiative
study including 8014 healthy women
having HRT showed a reduction in the
incidence of diabetes possibly related to
a decrease in insulin resistance. Data of
this trial indicate a small but significant
decrease in fasting glucose and fasting
insulin levels [13]. Margolis et al by using the HOMA-IR calculation to estimate insulin resistance showed a significant decrease in insulin resistance unrelated to body size [13].
Table 1 shows that studies analysing the
effects of estrogen administration on the
specific parameters for the evaluation of
the glucose metabolism have highlighted differences in relationship to the
dose or the route of administration.
Lobo et al. evaluated the effects of low
oral doses of Combined Equine Estrogens (CEE) 0.45 mg and 0.3 mg as compared to 0.625 mg and showed minimal
changes and differences among the 3
regimens [14]. The transdermal administration of estradiol (50 µg/day) to healthy
women reduced insulin levels and increased pancreatic C-peptide response to
glucose in one study, while another one
showed significant changes only in
hyperinsulinemic patients [15, 16]. The
trans dermal administration of estrogens
at high-doses seems to reduce post-hepatic insulin levels and to enhance the
insulin clearance by the liver, while the
effect of oral CEE on glucose metabolism is less evident [15, 17]. Some studies have shown only minimal positive
changes in the carbohydrate metabolism
[18, 19]. According to Karjalainen et al.
neither oral nor transdermal estradiol replacement therapy induces negative effects on glucose metabolism; both treatments induce only a small, but significant reduction in Glycated Hemoglobin
[HbA1c] levels and no change in postchallenge glucose and insulin levels.
Therefore treatment with high-doses
oral 17 beta-estradiol (E2) may determine a slight decrease of insulin sensitivity tested by hyperinsulinemic euglycemic clamp, while the transdermal
estrogen replacement alone in normoinsulinemic patients does not affect insulin sensibility [20].
These results were confirmed by our recent work showing that high doses oral
estrogen therapy (oral micronized estra-
diol 2 mg) caused a slight deterioration
in insulin sensitivity. On the contrary
low-doses unopposed estradiol treatment determine an improvement in the
peripheral insulin sensitivity made evident by an increase in the metabolic index (M) and a decrease of the insulin resistance index (HOMA-IR) [21].
Even in the case of low doses E2 oral
therapy associated with progestin, researchers did not show any impairment
of carbohydrate metabolism. Two recent
studies evaluating the effects of the 1 mg
E2/0.5 mg norethisterone acetate (NETA)
administration showed a decline in fasting glucose and insulin levels (above all
in women with higher basal fasting levels) and an amelioration in HbA1c and in
the OGTT responses in treated groups
respectively [22, 23].
In addition, studies exploring the effects
of estrogen administration in patients
with diabetes or metabolic syndrome
showed neither impact on glucose metabolism nor any improvement in insulin
resistance [24, 25]. Chu et al. in particular pointed out that transdermal E2 administration had more beneficial effects.
Recently a role has been suggested of the
timing of estrogen administration in relationship to the time of menopause. In
fact a longer interval between starting
treatment and the occurrence of menopause seems associated with a reduced
effect of E2 in increasing the whole body
glucose disposal and in improving insulin metabolism [26].
„ Estrogen and Lipid Metabolism
During their reproductive years, women
generally have levels of lipids (including
triglycerides) and LDL lower than men;
however, there is an increase after the
menopause [27]. By contrast, the difference in high HDL levels between men
and postmenopausal women remains the
same. These changes are in part due to
the age-related impairment of lipid metabolism, but may also be associated
with postmenopausal hyp estrogenism.
Estrogen effects on lipid metabolism
are mediated by estrogen receptor α
(ERα). It has been shown that polymorphisms of the ERα gene may influence
the lipid response after HRT [28, 29].
Estrogens are involved in both lipogen-
esis and lipolysis. At the transcriptional
level they increase the hepatic expression of apoprotein genes and the LDL
receptors and decrease the transcription
of the lipoprotein lipase (LPL) gene
through ERα. Thus, when estrogen levels decrease after the menopause, an increase of the LPL activity is observed
and this probably contributes to the increase of free fatty acids (FFA), as well
as to the accumulation of abdominal fat.
By inhibiting lipogenesis, estrogens alter the expression of hormone-sensitive
lipase [30]. On the other hand, through
ERα and estrogen receptor β (ERβ), estrogens are involved in the proliferation
of adipocytes, whereas their deprivation
increases central obesity which is associated with a more atherogenic profile
[31].
In general, menopause induces variations in lipoprotein plasma concentrations which are related to an increase in
cardiovascular risk. Epidemiological
data suggest a therapeutic role for estrogen replacement in the reduction of
coronary heart disease (CHD) after
menopause, with an improvement in
lipid status supposedly accounting for
25–50 % of this protective effect. However, estrogen substitution has both positive and negative effects [32]. Negative
effects are: increased occurrence of postprandial hyperlipidemia with increased
triglycerides, generation of atherogenic
of small LDL particles, increased risk of
inflammatory changes in vascular wall
and procoagulation effects. But estrogen
therapy increases the synthesis of all
lipoproteins including apolipoprotein
(Apo) B and increases the rate of their
metabolism in various degrees depending on the type of lipoprotein [33].
At present, considerable data have documented an increase in HDL and a reduction of LDL cholesterol following estrogen therapy [34]. Studies have clearly
established that estrogens decrease total
plasma cholesterol and increases or
maintains plasma triglyceride levels
[35–37]..
„ Estrogen Replacement
Therapy
Several reports have evaluated the effect
of postmenopausal hormone therapy on
lipid metabolism, but differences remain
in results and conclusions [38–40].
J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1)
121
Metabolic Impact of HRT
Table 2: Lipid metabolism and estrogen or hormone replacement therapy
Reference/Study
No. of
patients
Duration
Oral
CEE 0.625 mg or
CEE 0.625 mg + MPA
HERS study
ERA study
2763
256
12 months
38 months
È
È
Davidson et al., 2000 [58]
270
months
CEE 0.30 mg or
CEE 0.30 mg + MPA
Sanada et al., 2003 [49]
Mercuro et al., 2003 [50]
Lobo et al., 2001 [51]
Wakatsuki et al., 2003 [52]
Schlegel et al., 1999 [53]
51
25
749
51
39
96
Estradiol
Loh et al., 2002 [57]
(1 mg E2/0.5 NETA)
Hodis et al., 2003 [55]
(1 mg)
Angerer et al., 2002 [60]
(1 mg)
Alexandersen et al., 2001 [61]
Bruhat et al., 2001 [54]
(1 mg)
Hodis et al., 2001 [56]
(1 mg)
Davidson et al., 2000 [58]
Peeyananjarassri et al., 2005 [48]
Villa et al., 2008 [21]
(1 mg)
Villa et al., 2008 21]
(2 mg)
Chu et al., 2006 [25]
(1 mg)
Transdermal
Balci et al., 2004
(100 µg 17-β-E2/week)
Chu et al., 2006 [25]
(0.05 mg/die)
Salpeter et al., 2006 [68]
LDL HDL
Trygl
Ç
Ç
È
Ç
N(CEE);
Ç(CEE+MPA)
Ç
Ç
3 months
3 months
3 months
3 months
6 months
È
È
È
È
È
Ç
Ç
Ç
Ç
Ç
È
Ç
Ç
N
È
È
Ç
Ç
È
È
6 months
È
Ç
N
È
Ç
N
226
È
Ç
Apo-A1
Ç
321
48 weeks
È
Ç
N
301
440
12 months
6 months
È
È
Ç
Ç
N
Ç
È
Ç
Ç
È
È
Ç
Ç
Ç
48
months
months
3 months
N
N
N
N
48
3 months
È
Ç
N
50
3 months
È
Ç
N
43
3 months
È
Ç
È
50
3 months
È
N
311
18 months
È
Ç
222
270
N
ERT: estrogen replacement therapy; HRT: estrogen plus progesterone replacement therapy;
CEE: conjugated equine estrogen; MPA: medroxyprogesterone Acetate; 17β-E2: 17-beta-estradiol; N: no statistically significant change; Ç: increase; È: decrease.
Table 2 summarizes the principal studies
on the effect of estrogen replacement on
lipid parameters.
Two major placebo-controlled trials
have provided data on the effects of estrogen replacement therapy (ERT) on
the lipid metabolism: The Heart and
Estrogen/Progestin Replacement Study
(HERS) showed that LDL levels decrease from baseline while triglycerides
increase in the hormone treated group.
At the same time HDL levels increase in
the hormone group and decrease in the
placebo group [12]. The Estrogen and
122
Atherosclerosis (ERA) study, a placebocontrolled, randomized trial examined
the effects of CEE (0.625 mg/day) or
CEE (0.625 mg/day) plus MPA (2.5 mg/
day) on 256 post-menopausal women
with established coronary atherosclerosis; it showed a reduction in plasma remnant lipoprotein concentrations in the
context of no change or elevation in
plasma triglycerides levels in the active
treatment group with estrogen alone. A
significant increases in HDL-C and
Apo A-I levels has been observed [41,
42]. Authors of the study hypnotized that
the mechanism by which estrogens lower
J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1)
LDL-C and increase HDL-C concentrations is different from that of other lipidlowering medications and it may be the
key to the documented lack of protection
observed with estrogen replacement in
postmenopausal women with CHD.
Variations in treatment effects may be
attributable to the differences in baseline
characteristics among individuals and/or
also to differences in preparations, doses
and routes of hormone administration
[14, 43, 44].
Davidson et al. divided 270 women in
4 treatment groups (placebo, E2, E2/0.25
NETA, E2/0.5 NETA) and showed an increase in triglycerides, HDL cholesterol
and Apo A-I levels induced by unopposed 17β-E2 compared to placebo and
combined therapy. Moreover, in the E2
group, estrogen therapy which prevents
the increase in Lp(a) observed among
subjects taking placebo is consistent
with results from previous studies in
which reductions in Lp(a) have been observed with ERT [45].
Unopposed 17β-E2, despite lowering
LDL level, has little effect on Apo B
level and thus does not appear to reduce
the number of circulating atherogenic
lipoprotein particles. Estrogens increase
expression of hepatic LDL receptors, resulting in enhanced removal of LDL particles from the circulation and increase
the rate of very-low-density lipoprotein
(VLDL) secretion [46, 47].
Most differences observed may be due to
different doses of hormone administration.
A recent review analysed the effects of
low-dose hormone therapy on lipid metabolism. Studies comparing low-dose
(estrogens plus progestin) and standarddose hormonal therapy (HT) (estrogen
plus progestin) showed that CEE 0.3 mg
significantly increased levels of HDL
cholesterol and reduced levels of LDL
cholesterol and total cholesterol by the
same order of magnitude as standarddose HT [48–53].
Therefore widely different effects on
triglyceride levels have been observed.
In some studies triglyceride levels significantly increased with the higher doses
of CEE 0.625 mg and CEE 1.25 mg, but
Metabolic Impact of HRT
decreased with low-dose (CEE 0.3 mg)
[49, 53]; 1 study showed no difference
between CEE 0.3 mg and CEE 0.625 mg
doses while others showed that CEE
0.3 mg increased triglyceride levels as
much as standard-dose [50–52].
There was no dose-related effect on LDL
cholesterol or total cholesterol [50]. Significantly increased levels of HDL cholesterol and reduced LDL cholesterol
and total cholesterol were seen with administration of 1 mg of oral estradiol and
0.025 mg of transdermal estradiol [54–
59].
The effects of estradiol 1 mg on triglycerides were variable, with some studies
showing no change while others reporting a significant increase [54–61].
There were varying effects of HT on
Apo A-1. One study showed increased
Apo A-1 by both CEE 0.3 and 0.625 mg,
but another showed a decrease by CEE
0.3 mg [51, 53]. This study showed that
Apo B was decreased in both standarddose and low-dose HT while others
showed no change with low-dose HT but
a significant decrease with high-dose HT
[53, 58]. Finally Lp (a) was significantly
decreased by both the standard-dose and
the low-dose HT [50, 51, 53, 60]. The
reason for varying effects observed remains unclear.
Few studies have examined the effect of
estrogen therapy at different dosages on
lipid metabolism.
In a previous study [21], we evaluated
the different influences of 2 dosages of
oral formulations of unopposed E2 (1 mg
vs 2 mg) compared with a placebo treatment, both on glucose tolerance and
lipid metabolism in 48 healthy nonobese normoinsulinemic postmenopausal women.
The study showed that total cholesterol
level did not change, after treatment, in
all groups. Patients treated with 1 mg E2
showed no increase in triglycerides,
HDL-C and VLDL-C concentrations
after treatment, while a slight, but not
significant, decrease in LDL-C subfractions was noticed. This study showed
that the low-dose therapy did not adversely affect triglycerides plasma concentration. On the other hand, other beneficial effects on the lipoprotein profile
(increase in HDL cholesterol and decrease in LDL cholesterol levels, with a
significant reduction of the LDL/HDL
ratio) were observed in the E2-2 mg
treatment only. In contrast with previous
studies on unopposed low-dose oral estrogen treatment, our data showed only a
trend towards a decrease in LDL cholesterol levels, a neutral effect on the triglyceride levels and no change in the production of VLDL particles, which are
clearly involved in the atherogenesis
[63–66].
With regards to the route of estrogen
therapy administration, few studies analyzed the effect of transdermal therapy
on lipid metabolism. Balci et al. conducted a randomized, double blind trial
on hysterectomized women by administering transdermal E2 100 µg. Mean
serum HDL levels in the ERT group
were significantly higher than in control
group. Total cholesterol and LDL cholesterol showed an increase, while triglycerides levels were significantly decreased [67].
One of the few studies comparing the
effects of oral E2 (1 mg) or transdermal
E2 (0.05 mg) therapy on lipids was conducted in obese postmenopausal women
[25]. This study showed an increase in
HDL and a decrease in LDL with no significant change in triglycerides after oral
therapy. After transdermal therapy a non
significant increase in HDL and a decrease in LDL were observed. In summary, there were no changes in lipid parameters between oral and transdermal
therapy in women with metabolic syndrome.
A recent meta-analysis showed that oral
therapy produced greater reduction of
LDL/HDL ratio than transdermal therapy
but increased triglycerides levels. On the
contrary the transdermal therapy had an
overall neutral effect [68].
„ Conclusion
Overall the studies of ERT effects on
glucose and lipid metabolism are heterogeneous but all together the ERT impact
may be considered neutral. However,
low dose estrogen therapy may give
some beneficial effects. Above all the
treatment may prevent the physiological
worsening of the glucose and lipid metabolism.
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